WO2025174884A2 - Conjugués - Google Patents

Conjugués

Info

Publication number
WO2025174884A2
WO2025174884A2 PCT/US2025/015592 US2025015592W WO2025174884A2 WO 2025174884 A2 WO2025174884 A2 WO 2025174884A2 US 2025015592 W US2025015592 W US 2025015592W WO 2025174884 A2 WO2025174884 A2 WO 2025174884A2
Authority
WO
WIPO (PCT)
Prior art keywords
conjugate
linking group
calcitonin gene
radionuclide
related peptide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/015592
Other languages
English (en)
Other versions
WO2025174884A9 (fr
WO2025174884A3 (fr
Inventor
Thaddeus J. Wadas
Darpan Pandya
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Iowa Research Foundation
Original Assignee
University of Iowa Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Iowa Research Foundation filed Critical University of Iowa Research Foundation
Publication of WO2025174884A2 publication Critical patent/WO2025174884A2/fr
Publication of WO2025174884A9 publication Critical patent/WO2025174884A9/fr
Publication of WO2025174884A3 publication Critical patent/WO2025174884A3/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the Calcitonin Gene-Related Peptide Receptor is an important therapeutic target for a variety of disease states.
  • the CGRPR is a G-protein coupled receptor (GPCR) and member of the calcitonin receptor family (Russo, A. F. & Hay, D. L., Physiol Rev 103, 1565- 1644 (2023); and Russell, F. A., et al., Physiol Rev 94, 1099-1142 (2014)). It is comprised of the calcitonin-like receptor (CLR) and receptor activity -modifying protein 1 (RAMP1) subunit ( Figure 1).
  • the primary ligand of the CGRPR is calcitonin gene-related peptide (CGRP).
  • This receptor-ligand pair is involved or has emerging involvement with a variety of pathologies including migraine, peripheral pain conditions, cancer, inflammatory bowel conditions such as ulcerative colitis, arthritis, inflammation, infection and neuroinflammatory diseases such as Alzheimer’s disease (Russell, F. A., et al., Physiol Rev 94, 1099-1142 (2014); Ailani, J., et al., Neurology 99, 841-853 (2022); Balcziak, L. K. & Russo, A.
  • this innovative paradigm would 1) create a treatment strategy that does not rely on bone-remodeling pathways for efficacy; 2) be the first to study the effects of systemic radionuclide therapy on bone metastasis and CIBP and 3) provide a relationship describing the effects of each therapy class at the cellular, tissue and behavioral levels.
  • conjugates that bind to the CGRPR .
  • Such conjugates would be useful for treating diseases associated with the CGRPR and for imaging the CGRPR in a variety of systems to further elucidate its activity.
  • the present invention provides conjugates that bind to the calcitonin gene- related peptide (CGRP) receptor.
  • the conjugates are useful for treating diseases and conditions that are related to the calcitonin gene-related peptide (CGRP), which include cancer (e.g., prostate cancer, breast cancer, neuroblastomas, or neuroendocrine tumors), colitis, Crohn’s disease, pain, migraine, brain injury, and inflammatory bowel disease.
  • the conjugates are also useful as imaging agents (e.g., PET and SPEC imaging agents). For example, they can be used to image pain states, migraine, brain injury, and inflammatory bowel disease.
  • a conjugate comprising: a peptide that binds to the Calcitonin Gene- Related Peptide Receptor that is linked to a therapeutic or a detectable radionuclide is provided.
  • a wavy line “ ” that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.
  • terapéuticaally effective amount includes but is not limited to an amount of a conjugate of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • animal includes mammals, fish, amphibians, reptiles, birds and invertebrates.
  • mammal includes humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats.
  • the animal is a mammal.
  • the animal is a human.
  • patient refers to any animal including mammals.
  • the patient is a mammalian patient.
  • the patient is a human patient.
  • the atom to which the bond is attached includes all stereochemical possibilities.
  • a bond in a conjugate as described herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge)
  • a bond in a conjugate as described herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge)
  • the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted.
  • the conjugate may be at least 51% the absolute stereoisomer depicted. In another embodiment, the conjugate may be at least
  • the conjugate may be at least
  • the conjugate may be at least
  • the conjugate may be at least 99% the absolute stereoisomer depicted.
  • radionuclides and chelating groups are known, along with synthetic methods and synthetic intermediates that can be used to incorporate the chelating groups into conjugates. See Holik, H.A., et al., Molecules, 2022, 27(10), 3062. Additionally, radionuclides that are particularly useful for therapeutic applications as well as radionuclides that are particularly useful for imaging (e.g., PET and SPEC imaging) are known. Chelating groups that pair well with specific chelators are also known. See Holik, H.A., et al., Molecules, 2022, 27(10), 3062.
  • the chelating group is DOTA or DOTMA.
  • the chelating group is DOTA.
  • Radionuclides A variety of chelating groups and methods for their preparation are known, for example, see International Patent Application Publication Number WO2017/161356 (for example, pages 8-17 therein). Radionuclides
  • the radionuclide is suitable for PET imaging.
  • the radionuclide is selected from the group consisting of isotopes: n C, 18 F, 13 N, 15 0, 44 SC, 52 Mn, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 68 Ga, 76 Br, 82 Rb, 86 Y, 89 Zr, 94 Tc, 134 Ce, 149/152 ⁇ i34j ⁇ a , an j i24j j n
  • the radionuclide is selected from the group consisting of isotopes: 18 F, 64 Cu, 68 Ga, and 89 Zr.
  • the radionuclide is 64 Cu.
  • the radionuclide is 89 Zr.
  • the radionuclide is suitable for SPECT imaging.
  • the radionuclide is selected from the group consisting of isotopes: 67 Ga, n i In, 155 Tb 123 I, 125 I, 131 1, 203 Pb, and "Tc.
  • the radionuclide is selected from the group consisting of isotopes: 99 Tc, U1 ln, and 123 I.
  • the radionuclide is suitable for targeted radionuclide therapy (alpha, beta-emitters or auger).
  • the radionuclide is selected from the group consisting of isotopes: 67 Cu, 177 Lu, 89 Sr, 90 Y, 117 Sn, 131 I, 153 Sm, 166 Ho, 186 Re, 188 Re, 161 Tb, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ac, and 227 Th.
  • the radionuclide is selected from the group consisting of isotopes: 67 Cu, 90 Y, 177 Lu, 211 At, 212 Pb, 225 Ac, U 1 ln, and 227 Th.
  • the radionuclide is U1 ln, 177 Lu, or 225 Ac.
  • linking group is not critical, provided the final conjugate has the requisite properties for its intended use (e.g., as an imaging agent or as a therapeutic agent.
  • the linker can vary in length and atom composition and for example can be branched or non-branched or cyclic or a combination thereof.
  • the linker may also modulate the properties of the targeted conjugate such as but not limited to solubility, stability and aggregation.
  • the linker comprises about 3-5000 atoms. In one embodiment the linker comprises about 3-4000 atoms. In one embodiment the linker comprises about 3-2000 atoms. In one embodiment the linker comprises about 3-1000 atoms. In one embodiment the linker comprises about 3-750 atoms. In one embodiment the linker comprises about 3-500 atoms. In one embodiment the linker comprises about 3-250 atoms. In one embodiment the linker comprises about 3-100 atoms. In one embodiment the linker comprises about 3-50 atoms. In one embodiment the linker comprises about 3-25 atoms.
  • the linker comprises about 10-5000 atoms. In one embodiment the linker comprises about 10-4000 atoms. In one embodiment the linker comprises about 10-2000 atoms. In one embodiment the linker comprises about 10-1000 atoms. In one embodiment the linker comprises about 10-750 atoms. In one embodiment the linker comprises about 10-500 atoms. In one embodiment the linker comprises about 10-250 atoms. In one embodiment the linker comprises about 10-100 atoms. In one embodiment the linker comprises about 10-50 atoms. In one embodiment the linker comprises about 10-25 atoms.
  • the linker comprises atoms selected from H, C, N, S and O.
  • the linker comprises atoms selected from H, C, N, S, P and O.
  • the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 1000 (or 1-750, 1-500, 1-250, 1-100, 1- 50, 1-25, 1-10, 1-5, 5-1000, 5-750, 5-500, 5-250, 5-100, 5-50, 5-25, 5-10 or 2-5 carbon atoms) wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -N(R a )-, 3-7 membered heterocycle, 5-6-membered heteroaryl or carbocycle and wherein each chain, 3-7 membered heterocycle, 5-6-membered heteroaryl or carbocycle is optionally and independently substituted with one or more (e.g.
  • the linker comprises a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from about 1 to 1000 (or 1-750, 1-500, 1-250, 1-100, 1- 50, 1-25, 1-10, 1-5, 5-1000, 5-750, 5-500, 5-250, 5-100, 5-50, 5-25, 5-10 or 2-5 carbon atoms) wherein one or more of the carbon atoms is optionally replaced independently by -O-, -S, -N(R a )-, , wherein each R a is independently H or (Ci-Ce)alkyl.
  • the linker comprises one or more amino acids or peptides. In one embodiment, the linker comprises at least one amino acid. In one embodiment, the linker comprises at least two amino acids. In one embodiment, the linker comprises at least three amino acids.
  • the linker comprises 10-100 atoms selected from H, C, N, S and O. In one embodiment, the linker comprises 10-100 atoms selected from H, C, N, S and O, including one or more amino acids.
  • the linker comprises 10-50 atoms selected from H, C, N, S and O.
  • the linker comprises 10-50 atoms selected from H, C, N, S and O, including one or more amino acids.
  • the linker is covalently bonded to the chelating group through a nitrogen atom of the linker. In one embodiment, the linker is covalently bonded to the chelating group through the methylene of a 4-benzyl group.
  • the linker is covalently bonded to the N-terminus of the peptide that binds to the Calcitonin Gene-Related Peptide Receptor through a carbonyl group of the linker forming an amide bond.
  • the linker comprises 10-50 atoms selected from H, C, N, S and O; the linker is covalently bonded to the chelating group through a nitrogen atom of the linker; and the linker is covalently bonded to the N-terminus of the peptide that binds to the Calcitonin Gene-Related Peptide Receptor through a carbonyl group of the linker forming an amide bond.
  • the linker comprises 10-50 atoms selected from H, C, N, S and O; the linker is covalently bonded to the chelating group through a methylene of a 4-benzyl group of the linker; and covalently bonded to the N-terminus of the peptide that binds to the Calcitonin Gene-Related Peptide Receptor through a carbonyl group of the linker forming an amide bond.
  • the linker comprises:
  • the linker comprises: wherein n is 0, 1, 2, 3, 4, 5, or 6. In one embodiment, the linker is: wherein n is 0, 1, 2, 3, 4, 5, or 6.
  • the linker comprises a ring that can be formed using click chemistry.
  • the linker comprises 10-50 atoms selected from H, C, N, S and O and includes a ring that can be formed using click chemistry.
  • the peptide that binds to the Calcitonin Gene-Related Peptide Receptor is an antagonist of the Calcitonin Gene-Related Peptide Receptor.
  • the conjugates can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the conjugates are administered intravenously or intraperitoneally.
  • “Secular equilibrium” is defined as the point in which the quantity of a radioactive isotope remains constant because its product rate equals its decay rate. In the radiopharmaceutical solutions described herein, secular equilibrium is considered to be reached when the quantity of daughter isotopes for an alpha emitting radionuclide are considered to remain nearly constant. In some embodiments, the chelate solution is maintained at about 25 degrees Celsius for at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours, or at least 24 hours until secular equilibrium is reached.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • the pH of the resulting solution was adjusted to 5.5-6 using 1 M Tris buffer (10-12 pL), and then incubated at 60°C for 1 hour. Reaction progress and radiochemical purity of were measured without further purification using, radio-TLC, gamma counting of radio-HPLC fractions, or radio-HPLC.
  • In vitro serum stability was carried out by adding 50 pL of the radiopharmaceutical (2 MBq) to 900 pL of human serum.
  • PBS phosphate buffered saline
  • Figure 11 shows the biodistribution of [ n i In]In-l in selected tissues. This data was collected at 1 hour, 4 hours, and 24 hours. This data demonstrates that the radiopharmaceutical rapidly excretes from the blood pool and has low to modest retention in Liver, Kidney and bone tissues. This pharmacokinetic data is consistent with the excretion profiles of other peptide-based radiopharmaceuticals.
  • %ID/g Percent injected dose/gram
  • Figure 12 shows the tumor-to-muscle ratio of tumor-bearing mice injected with [ i n In]In-l at 4 hours post-injection.
  • the tumor/muscle ratio was excellent, suggesting improved selectivity for CGRPR + tissues over CGRPR' tissues.
  • the ratio is significantly diminished upon co-inj ection of blockade with peptide chelator conjugate 1. This reduction in the tumor-to-muscle ratio suggests a receptor mediated interaction between the radiopharmaceutical and the CGRP receptor in vivo, and that the radiopharmaceutical is interacting with the receptor as desired.
  • the HTB-10 cell line is a neuroblastoma cell line that endogenously expresses the CGRPR. It is considered a canonical cell line that is used in CGRPR research. Studies were completed as described by Pandya, D. et al., Theranostics 6, 698-709 (2016).
  • the [ 177 LU]LU-1 treatment group received two doses and each dose consisted of 500 microcuries of the radiopharmaceutical.
  • the non-radioactive peptide group (Group B) received a mass of peptide that was consistent with the mass of peptide injected in Group C. Animals were removed from the study once clinical end points were met. Those endpoints were tumors that exceeded 2000 mm 3 or that were ulcerated. Animals receiving the radiopharmaceutical (Group C) had a significant survival benefit when compared to those animals not receiving the radiopharmaceutical (Groups A and B).
  • the cohorts received intravenous injections of either saline, the non-radioactive peptide chelator conjugate 1 or [ 177 Lu]Lu-l (Verhoeven, M., et al., Mol Imaging Biol 26, 114-123 (2024); Berglund, H., et al., Eur J Nucl Med Mol Imaging 51, 768-778 (2024); and Mohajershojai, T., et al., Cancers (Basel) 15 (2023)). Animals were monitored daily for signs of distressed behavior. Cohorts were followed until clinical endpoints ( tumor volume > 2000 mm3 or ulcerated tumor) were reached. As animals reached clinical endpoints they were euthanized.
  • Tissues were harvested and stained with anti-Ki-67 or anti-caspase-3 to assess cell proliferation and apoptosis, respectively. Tissues can also be stained with anti-CGRPR, anti-LC3B, or anti-P-galactosidase mAbs (Abeam, Inc.) to assess CGRPR expression, autophagy, and senescence, respectively.
  • Ki-67 Ki-67 is a way to measure how fast cancer cells in a tumor are dividing. Ki-67 is a protein that is found only in cells that are dividing. A high Ki-67 proliferation index means many cells are dividing quickly and that the cancer is likely to grow and spread.
  • mice treated with radiotherapy exhibited lower staining intensities within their tumors when compared to mice treated with saline or peptide chelator conjugate 1. This suggests that the radiotherapy exerted a therapeutic effect and reduced cell proliferation within the tumors.
  • Tissues were harvested at the time of euthanasia and embedded in optimum cutting temperature (OCT) compound (Miles, Inc., Elkhart, IN). Frozen sections (4-6 pm) were cut, fixed in ice-cold acetone, and stained using procedures similar to those described by Pandya, D. N., et al., Theranostics 6, 698-709 (2016); and Graefe C, et al., Mol Biol Rep. Aug;46(4):4631-4643 (2019).
  • OCT optimum cutting temperature
  • Caspase-3 is a biomarker for apoptotic cell death. Caspase-3 staining of HTB-10 tumor sections and histological analysis revealed that mice treated with radiotherapy exhibited higher staining intensities within tumors when compared to mice treated with saline or peptide chelator conjugate 1. This suggests that the radiotherapy exerted a therapeutic effect that increased the amount of cell death (apoptosis) within the tumor.
  • radiochemical purity and serum stability were confirmed using procedures similar to those described by Pandya, D. N., et al., Theranostics 6, 698-709 (2016). Data is shown in Figures Briefly, radiochemical purity of each radiopharmaceutical was measured without further purification using radio-TLC, which was conducted on a Bioscan AR 2000 radio- TLC scanner equipped with a 10% methane: argon gas supply and a PC interface running Winscan v.3 analysis software (Eckert & Ziegler, Berlin, DE). Varian ITLC-SG strips were employed using a 0.9% NaCl/10 mM NaOH and 30:70 10% NEUOAc/methanol solution as eluents.
  • In vitro serum stability was carried out by adding 50 pL of each radiopharmaceutical to 900 pL of human serum.
  • compositions disclosed herein can comprise between about 0.1 % and about 45%, and especially, about 1 and about 15%, by weight of the total of one or more of the compounds based on the weight of the total composition including carrier or diluents.
  • dosage levels of the administered active ingredients can be: intravenous, about 0.01 to about 20 mg/kg; intraperitoneal, about 0.01 to about 100 mg/kg; subcuta-neous, about 0.01 to about 100 mg/kg; intramuscular, about 0.01 to about 100 mg/kg; orally about 0.01 to about 200 mg/kg, or about 1 to about 100 mg/kg; intranasal instillation, about 0.01 to about 20 mg/kg; and aerosol, about 0.01 to about 20 mg/kg of animal (body) weight.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne un conjugué comprenant un peptide qui se lie au récepteur peptidique lié au gène de la calcitonine qui est lié à un radionucléide thérapeutique ou détectable. Les conjugués sont utiles pour imager le récepteur peptidique lié au gène de la calcitonine et pour traiter des maladies dans lesquelles l'activité du récepteur peptidique lié au gène de la calcitonine est impliquée.
PCT/US2025/015592 2024-02-14 2025-02-12 Conjugués Pending WO2025174884A2 (fr)

Applications Claiming Priority (2)

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US202463553499P 2024-02-14 2024-02-14
US63/553,499 2024-02-14

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WO2025174884A2 true WO2025174884A2 (fr) 2025-08-21
WO2025174884A9 WO2025174884A9 (fr) 2025-10-02
WO2025174884A3 WO2025174884A3 (fr) 2025-11-13

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US10925977B2 (en) * 2006-10-05 2021-02-23 Ceil>Point, LLC Efficient synthesis of chelators for nuclear imaging and radiotherapy: compositions and applications

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WO2025174884A3 (fr) 2025-11-13

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